The synthesis of structurally diverse libraries of small molecules is a key requisite for the realization of the NIH Molecular Libraries Roadmap program. Within the past years we have established a robust synthesis platform for solid phase synthesis. Based on this technology we have successfully developed a number of diversity-oriented synthetic pathways that were realized in the synthesis of split-pool small molecule libraries in a "one bead, one stock solution" format. The libraries are designed in a way that allows follow up chemistry for activity optimization. Many of these libraries were screened in multiple biological assays. Some of these libraries proved to be compatible with typical screening conditions and produced potent hits in various disease-related assays. Our objectives are the translation of three libraries from a one bead (0.05mg) platform to our newly established platform that will deliver >10mg of purified compound per library member. The selected libraries are based on a) macrolides of varying ring size, b) natural product-like spirooxoindol core structures and c) a dihydropyran carboxamide scaffold. Each library has been demonstrated to exhibit both excellent long term stability and compatibility with biological media. We will select a representative subset of these libraries (~ 800 compounds/library) that retains a maximum of the chemical diversity. We will synthesize and purify these libraries and transfer the compounds, including detailed experimental information, to the NIH Small Molecule Repository for screening in a multitude of assays. These screens will be relevant to a number of diseases including cancer, viral infections and metabolic disorders. Library members that are identified as hits can serve two major purposes: 1) Active compounds can be used as probes to study the disease in order to develop new therapeutic approaches, 2) screening positives can serve as lead structures for the development of novel drugs. [unreadable] [unreadable]